Diamino-pyrimidine compositions for chemotherapy of coccidiosis



2,895,874 Patented July 21, 1959 DIAMINO-PYIDINE COMPOSITIDNS FOR CHEMUTHERAPY OF COCCIDIOSIS No Drawing. Application March 27, 1953 Serial No. 345,252

12 Claims. (Cl. 16753.1)

This invention relates generally to the art of veterinary medicine and more particularly to the chemotherapy of the disease in poultry known as coccidiosis.

Coccidiosis in poultry ranks in the forefront with those diseases which are most destructive and causes very large annual economic losses. Coccidiosis is a protozoan infection, commonly occurring between the ages of two to fourteen weeks in poultry. The disease organisms multiply in the digestive tract, particularly in the intestine. Disease symptoms are characterized by bowel disorders, hemorrhage, anemia and general unthriftiness. Mortality is generally substantial, varying with the severity of infection.

Two common types of coccidiosis are known: the cecal, caused by the coccidium Ez'meria tenella, and characterized by a severe hemorrhage on or about the fifth day after infection; and the intestinal caused by at least seven types of Eimeria; namely, E. acervulina, E. necatrix, E. maxima, E. hagani, E. mitis, E. praecox, and E. brunetti. The intestinal type is generally referred to as the chronic, and the cecal as the acute.

Various therapeutic preparations have been used to lessen the severity of the losses associated with the disease. Our general experience has been that those preparations now commercially available have one or more of the following drawbacks or failings: Their effectiveness in suppressing or treating the disease is not high; quite often the high use levels required impose an economic burden on the user; the drugs may function only as a prophylactic and not as a control for an established infection; their use may be attended by certain undesirable side effects, namely, toxicity, as evidenced by lowered weight gains and feed consumption.

It is an object of this invention to provide an eifective therapeutic control of coccidiosis in poultry which largely overcomes the above-mentioned disadvantages of treatments heretofore used. This invention provides compositions which may be fed to poultry in very small yet effective dosage without discernible unwanted side effects. The very low use levels make their use extremely economical. Furthermore, mortality due to severe infections of coccidiosis in poultry may be reduced to nil, or at least to We have discovered that certain compounds belonging to the chemical class known as diamino-pyrimidines are effective to control infections of coccidiosis when fed to the poultry in an ingestive vehicle in very low concentrations. An what is probably more significant, we have discovered that certain of the diamino-pyrimidines effectively synergize certain of the sulfonamide drugs so that infections of coccidiosis may be controlled when a combination of these diamino-pylimidines and these sulfonamides are mixed in very low concentration with an ingestive vehicle. Ingestive vehicles as used herein will be understood to mean feed or drink normally partaken by poultry such as grain, mash, scratch, water or other liquids. This synergism is surprising, in view of the fact that although sulfonamide drugs have heretofore been suggested and used in the control of coccidiosis, some of them by themselves are relatively ineffectual against coccidiosis and even these are rendered extremely efie'ctive in the synergistic combination. By virtue of this synergism, percentages of the diarnino-pyrimidine and the sulfonamide are possible far below those which would have to be used if either of them were used alone to achieve the same end, even in the case of sulfonamides known to be useful in the treatment of coccidiosis. That is, the dosage of sulfonamide which would normally be recommended and used for control of coccidiosis can be reduced to 1/10 to l/ of the normal dosage when used in the synergized combination of the diamino-pyrimidine and the sulfon-amide. And it is particularly surprising that by combining the diamino-pyrimidine with a sulfonamide, such, for example, as sulfanilamide, which is relatively ineffective alone as a coccidiostat, the otherwise inactive sulfonamide becomes effectively active as a coccidiostat.

The diamino-pyrimidines that we have found to be active compounds for the treatment and control of coccidiosis in poultry are those of the general formula:

in which R is H, or a lower n-alkyl group containing one to five carbon atoms inclusive, and Ar is an appropriately substituted phenyl group; efiective substituted phenyl groups include p-chlorophenyl and 3,4 dichlorophenyl.

The compounds which we have found to be particularly useful as coccidiostats belong to the class described chemically as 2,4-diamino-5-(p-chlorophenyl)-6-(alkyl)-pyrimidines (where the alkyl contains a straight chain of one to five carbons inclusive). We have found that when fed to poultry in feed mash the optimum use level is .0035 to .015 administered as a prophylactic and 0.25% to 029% administered as a treatment. These percentages are considerably lower than those permissible with most medications which have heretofore been commercially available.

Moreover, we have found that mentioned in the two preceding paragraphs are effective synergists for certain sulfonamides so that the therapeutic activity of the sulfa drugs may be effectively enhanced when a diamino-pyrimidine is administered together with a sulfonamide or the diamino-pyrimidines a mixture of sulfonarnides and the dosage may be considerably less than the dosage required if only one of these substances were administered.

The use of sulfonamides for treating coccidiosis has been practised for more than a decade. Some are known as effective coccidiostats, others are ineifective and others are of intermediate effect in their activity. Generally high levels, viz., concentrations, were required, until the more recent N-pyrimidyl types appeared. The most successful sulfonamide so far developed for treatment of coccidiosis appears. to be sulfaquinoxaline. This has permitted comparatively low use levels: 0.15 as a propylactic; .05% as a treatment of an established infection when administered in an ingestive vehicle such as mash feed.

Notwithstanding the eifectiveness' of the various sulfa drugs used or suggested as coccidiostats and their varying optimum or permissible use levels, we have found that whichever of the sulfonamides that may be selected for use as a remedy for the treatment of coccidiosis, their activity may be enhanced by use in conjunction with them of the diamino-pyrimidines herein mentioned as having the desirable synergistic activity so that a preparation may be produced which is effective in lower concentration (in an ingestive vehicle) than if the sulfas selected were used alone as a coccidiostat.

Consequently the coccidiostatic preparation comprising a combination of a synergistic diamino-pyrimidine and one or more sulfonamides as contemplated by the invention has decided advantages. sulfonamides, such as sulfanilamide, may be rendered substantially the equal of the present-day sulfaquinoxaline medication, and, secondly, smaller dosages of sulfonamides may be used. For example, we have found that' sulfamerazine is active at M the usual dosage when synergized by the addition of 2,4-diamino-5-(p-chlorophenyl) -6-ethyl pyrimidine.

The use and effectiveness of the diamino-pyrimidines both alone and with sulfa drugs (viz., sulfonamides) have been tested in varying relative amounts and concentrations or use levels. In conducting screening tests to determine activity of the various diamino-pyrimidines mentioned and combinations of the diamino-pyrimidines and sulfa drugs, the following described procedure was used: A large number of chicks three to four weeks-of age, divided into groups, are infected by administering to them orally equal amounts of coccidiosis cocysts, such as E. tenella. This infection will result in a certain percentage of mortality in five to eight days, if the-chicks do not receive a drug which is therapeutically active in suppressing the infection. Each group of infected chicks is given a compound being tested and in each test is included a group of the same flock of chicks which were not given any medication (this group being designated an unmedicated. control) and also included is a group of infected chicks to which is administered a drug heretofore known to be one active to suppress coccidiosis (this group being designated as a medicated control). In thisway results with a group of chicks receiving the compound being tested can be compared with both of the control groups.

An infection of E. tenella will also produce a certain amount of damage or lesions to the cecal walls. These are evaluated in the tests on each chick that dies during the course of the test. After eight days several survivors from each group are sacrificed for autopsy and the cecal lesions evaluated; Accordingly, in'addition to comparing mortality rates in the groups, a comparison of cecal lesions of the test compound group with the control First, relatively inactive groups serves as a basis for determining therapeutic activity.

In some instances in the tests, the test compound was administered before the chicks were infected and in others it was administered after infection. For example, in the tables which appear hereinafter under the column Conditions, +24 indicates that the drug dosage was started twenty-four hours before infection, while -48" indicates that it was started forty-eight hours after infection. This serves to determine whether the compound is therapeutically active in suppressing an infection which is already established or only in preventing the occurrence or spread of cecal coccidiosis in a flock.

The compounds being tested were administered by including them in the mash and in some instances in the drinking water in amounts onconcentrations as indicated in the tables hereinafter. That is, the birds consumed the compounds together with the carrier vehicle ad libiturn.

The results of illustrative tests are set forth in the tables and this data will serve to show the activity of the compounds listed in combatting or suppressing coccidiosis at different use levels.

Drug tested-[2,4-diamino5-(p-chlorophenyD-fi-methyl pyrimidine] Drug used in medicated control .0

mash... water...

as o wwow we: .a I-IQ oooooooooon occoeq tested-[2,4-diainin0 6-n-am y1-5- (pchloroph cnyl) -pyrim idine] Drug used in medicated control v(M;O.)-n1troiuraz0no 11121511.... 50 +48 rdo... 0 +48- o 18 +1:

Drug:tested-[2;t-diainino-5-(3,4-dicbl0rophenyl)-6-methyi pyrimidine] Drug used in medicated control (M.C.)suliaquu10xahne Intheforegoing Table I; U.M.C. indicates a. group that was not given any drug and is designatedxas an unmedicatedcontrol; M.C. designates a medi'catcdcontrol, the drug used being set forth beneath the name of' the drug used in the test. The column designated. Conditions indicates the time before or' after in hours the group of'chicks was infectedwith E. tenella cocysts, the sign indicating before infection, the sign indicating after infection. The column Ingestive Vehicle? indicates themanner of administering the drug. The column Mortality showsthe number (expressed in percent) in the particular group that have died during an eight-day period. The column Cecal Lesions indicates the sever- 2, 05, are

The above figures refer to s-called treatment levels of the medications. These percentages, when analyzed, it is possible to cut the normal coccidiostatic active In controlling coccidiosis 1n poultry when fed in an Furthermore, it is possible to cut the percentage of diingestive vehicle at optimum use levels of 0035 to amino pyrimidine to less than the values shown, if this 015% when administered as a prophylactic and 25% to deficiency is remedied by increasing relatively the dosage to 029% administered as a treatment of an infected flock ofsulfa. but also that these diammo-pynmidines are eifective The following Table II sets forth the data and results synergists for the sulfonamides so that the therapeutic acof illustrative tests with respect to the synergistic combillvlty 0f the Sulfa drugs y be wely enhanced when nations. The tabulated data are from tests conducted in the drugs are used In Combination and in comblnatloll the similar manner as described above in connection with dvsage y n y less than the dosage if y Table I The following Index 18 an index of the Roman one of them is administered. numerals appearing in the tablgs;

It has been establlshed that the sulfonamide drug in the combination may be varied over wide concentration Index ranges and efiectiveness is still retained. The following v tabulation illustrates effective combinations. Be it noted I-designates 2,4 diamino 5 (p chlorophenyl) dthat these examples are merely illustrative of the principle ethyl pyrimidine. of the invention, and are not to be construed as limiting 2O III designates 2,4 diamino 5 (p-chlorophenyl) 6- the invention to these combinations alone. methyl pyrimidine.

. I XVIL-designates 2,4 diamino- 5 (p chlorophenyD- Synergist, Percent Limits Sulfa, Percent Limits 6-propyl pyrimidine.

XVIII-designates 2,4 -diamino 6 -methyl 5 (p- Sulfanilamide .04-,4 nitrophenyl) pyrimidine. 512,4. Sulf tln' le .02-.2 1 fiii finlfim fiiifiif. 002-. 01 sulf me r ineuh. .005-. 05 IIdes1gnates sulfaqulnoxaline. ethylpynmldmeggggi figg: 8gff X-designates sulfamerazine. sy st sflA-dia inoow-05 XIV-des1gnates sulfamethazme. 3ii 1?5 l3" 00km {sulfaquinoxeline .0005-025 XIX- designates sulfathiazole. fi g fg iig'ff gfig gj 0% 02 {Sulfamerazine.- .005-. 05 XX-designates sulfanilamide. phenyb pyrin iidine. sulmqummalme" XXIH-designates sulfadiazine.

XXIV-designates sulfaguanidine.

TABLE II Synergist, Sulfonamide, Mor- Oecal Test N 0. Ref. No. Percent Percent tality, Lesions Percent 0 80 .005 I .01 II 0 .0075 III .01 II 0 trace .01 11 1 .01 I5 28 +++i 0 .4 XIV ,0 0 .005 I .0033 II 0 trace .005 I 0133 XIV o trace 0 0 20 0 .5 X 0 0 .006 I .016 X 0 trace .005 I .0084 X 0 .005 I .005 X 0 .0055 I .0125 X 0 .0035 I .0125 X 0 .0022 I .0125 X 0 0 0 20 +++-l- 0 .037 II 14 .005 I .015 X 0 .005 I .0033 II 0 0 4O o .05 II 0 .01 I .0157 X 0 .01 I .008 0 .01 I 025 XIX 0 .01 I .05 XX 0 trace 0 30 .0055 I .0005 II .0055 I .001 II 10 .0055 I .0015 II 10 .01 I .01 II 0 trace .003 I .01 II 0 .003 I .02 1g 88 i -i 0 .05 II 0 .004 I .0075 II 20 .005 I .0075 II 0 .004 I .01 II 0 .005 I .01 II 0 .004 I .015 II 0 .005 I .015 II 0 0 0 a0 005 XVII .01 II 20 075 XVII .01 II 0 0 0 05 II 0 .01 XVIII .01 II 0 0 0 50 0 .05 II 0 .0075 I .02 XXIII 0 0 .0075 I .02 XXIV 0 diamino-6-methyl-5 -(p-nitrophenyl) -pyrimidine of 2,4-diamino--(p-chlorophenyl) -6-propyl compounds mentioned herein.

I ing diamino-pyrimidines. those skilled in the art that the use levels of therapeutic difierent circumstances.

low levels (low concentration) of an active (the first 8 to r f In the tests tabulated above the drugs were administered by mixing them in the feed mash, that is, the birds were allowed to feed ad libitum on this ration. However, if desired, the drugs may be administered by medicating the drinking water, that is, by allowing the birds to partake ad libitum of this ration. The following Table III sets the drugs'were administered by putting them in the drinking water which was set before the chicks. V phenyl)'-6-ethy1 pyrimidine was solubilized by preparing a concentrate consisting of 1.14 grams of the compound, 235 ml. ethyl alcohol, 125 ml. Tween 60 (a commercial wetting agent). The sulfaquinoxaline used was a commercial product Quinatrol-ZS which contains 25% sulfaquinoxaline.

TABLE 111 Percent Percent Mor- Group DAP Sulfa tality, Lesions percen 1 2,4-diamino-5-(p-ehlorophenyl)-G-ethyl-pyrimidine.

i Suliaquinoxaline.

The following Table IV sets forth tabulative comparative results of another illustrative test showing the nature of the synergistic combination of a diamino-pyrirnidine and a sulfa drug.

TABLE IV V Ingestlve or- Cecal Vehicle .05 II 90 .01 II and 01 XVIII. 84 .015 II and .0075 +24 XVII.

Table IV the Roman numerals represent the drugs as indexed in Table II and otherwise the data is recorded in the same way as in Table II. It will be seen that the use of a combination of .0l% sulfaqninoxaline and .01% of 2,4-diamino-6-methyl-5-(p-nitrophenyl)- pyrimidine produced a better result than 05% of 2,4-

alone and as good a result as .05% sulfaquinoxaline alone, this showing the synergistic action of the combination. Also, a combination of 015% of sulfaquinoxaline and'.0 075% pyrimidine produced as good results as 05% sulfaquinoxaline alone and better results than .02% of2,4-diamino-5-(p-chlorophenyl)-6-propyl pyrimidine alone. 1 v

It will be understood by those skilled in the art that it is the base that is the physiologically active part Consequently, the salts such as the acid addition salts, and other similarrnodifications of the diarnino-pyrimidine compounds referred to herein are to be regarded as equivalents of the correspond- It will also be understood by In the above agents of the nature herein disclosed will vary under It is common practice in many quarters to use during the growing period 12 weeks for chickens) to control the amount of infection which may develop in a flock during the growing'pe'riod. Consequently, chicks which are exposed to a small amount of infection become immune to cecal coccidiosis and tality, perceu I 1 by weight of a diamino-pyrimidine having the formula:

' alkyl group containing one o oo o sudden attacks and losses are avoided or minimized. Drugs used in this manner are spoken of as prophylactic. They are prophylactic to the degree that they limit the development of the infection. On the other hand, in those cases where the flock has become badly infected higher use levels may be necessary to combat and suppress the infection. The therapeutic agents provided by the invention lend themselves for use in either situation and are eifective both as prophylactic at low use levels and at higher use levels without undue toxic effect for combatting and suppressing an established case of the disease. Those skilled in the art will also understand that use level" means the concentration of the therapeutic'compound in the ingestive carrier vehicle fed to the poultry in order to administer the active compound and the use level must be such that it does not exceed a concentration which is unduly toxic.

The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalent of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of invention claimed.

What is claimed is:

l. A ration for ad libitum feeding to a flock of poultry to combat the disease of coccidiosis in the poultry flock without intolerable toxic effect upon the poultry which comprises a poultry feeding mash in which is incorporated Lesions not less than .002 percent and not more than .05 percent H N R where R is selected from the class consisting of H and an to five carbons inclusive and Ar is selected from the class consisting of p-chlorophenyl and 3,4-dichlorophenyl.

of the which may be fed to the poultry as a V and consumed ad libitum for the control of coccidiosis in poultry which comprises a mixture of a poultry feeding mash and a coccidiostat ingredi- 2 A composition ent comprising a diamino-pyrimidine compound selected 7 from the class consisting of 2,4-diamino-5-(p-chlorophenyl)-6-ethyl pyrimidine;

, S-(p-chlorophenyl)-pyrirnidine,

phenyl)-6-methyl pyrimidine; 2,4-diamino-5-(p-chloro- 2,4-diamino-6-n-amyl-5-(pchlorophenyl)-6-ethyl-pyrimidine, 2,4-diamino-6-n-amyland 2,4-diamino-5-(3'4'- dichlorophenyl)-6-methyl pyrimidine, said mixture containing not less than .002 percent and not more than .05 percent by weight of said coccidiostat ingredient whereby be administered in effective "dosage and at a use level which allows the poultry to I feed ad libitum on the mixture without intolerable toxic effect.

3". A chemotherapeutic composition for the control of sulfonamide selected from the class consisting of sulfacoccidiosis in poultry which comprises a mixture of a quinoxaline; sulfamerazine; sulfamethazine; sulfathiadiamino-pyrimidine selected from the class consisting of role; sulfanilamide; sulfadiazme, and sulfaguanidine, and 2,4-diamino--(p-chlorophenyl)-6-methy1 pyrimidine; 2,4- a 2,4-diamino-5-(p-chlorophenyl)-6-(alkyl)-pyrim.idine diamino-S-(p-chlorophenyl)-6-ethy1 pyrimidine; 2,4-di- 5 having 1 to 3 carbon atoms in the alkyl group which is amino-S-(p-chlorophenyl)-6-n-propyl pyrimidine; 2,4-diactive synergistically with the sulfonamide in said amino-6n-amyl-5-(p-chlorophenyl)-pyrimidine; 2,4-dimixture. amino-5-(3,4'-dichlorophenyl)-6-methyl-pyrimidine, and 8. A composition efifective to control coccidiosis in 2,4-diamino-6-methyl-5-(p-nitro-phenyl)-pyrimidine; and poultry which composition when diluted with a nonsulfonamide selected from the class consisting of sulfa 10 toxic ingestive comestible carrier will provide an effecquinoxaline; sulfamerazine; sulfamethazine, sulfathiazole; tive dosage when orally administered by feeding it to the sulfanilamide; sulfadiazine, and sulfaguanidine, said poultry in the comestible in a concentration of less than mixture being so proportioned with respect to its content 0.5 said composition comprising a mixture of one or that a predetermined quantity of said mixture may be sulfaquinoxaline; sulfamerazine; sulfamethazine; sulfaintimately intermixed with a predetermined quantity of thiazole; sulfanilamide; sulfadiazme, and sulfaguanidine, mash to form a poultry ration on which poultry may feed and a 2,4-diamino-5-(p-chlorophenyl)-6-(alky1)-pyrimiad libitum without intolerable toxic effect and which dine which is active synergistically with the sulfonamide will contain the diamino-pyrimidine and sulfonamide in in said mixture. effective dosage amounts but not exceeding .02 percent 9. A chemotherapeutic feed ration for combatting the by Weight of diamino-pyrimidine and not exceeding 0.4 disease of coccidiosis in poultry on which the poultry percent by Weight f lf id may feed ad libitum comprising a poultry feed mash, 4. A chemotherapeutic composition for the control of sulfaqllilloXalif-le and m -(P- Ph BYD- idi i i poultry hi h comprises a i ture of a ethyl pyrimidine, the sulfquinoxaline being present in the diamino-pyrimidine selected from the class consisting of mixture in the ratio of .5 to 20 parts to 1 part of diamino- 2,4-diamino-5-(p-chlorophenyl)-6methyl pyrimidine; 2,4- pyrimidine and the combined amounts of said sulfaquindiamino-5-(p-chlorophenyl)-6-ethyl pyrimidine; 2,4-dioxaline and diamino-pyrimidine not exceeding .06% by amino-S-(p-chlorophenyl)-6-n-propyl pyrimidine; 2,4-dight 0f id mash. amino-6-n-amyl-5-(p-chlorophenyl)-pyrimidine; 2,4-di- 10. A chemotherapeutic composition for combatting 3m1'110-5-(3',4'-dich1oropheny1)-fi-methyl pyrimidine, and the disease 0f COCCiCllOSlS in poultry Which comprises a 2,4-diamino-6-methyl-5-(p-nitrophenyl)-pyrimidine; and mixture of -(P- P Y y PY ulfonamjde elected from the class consisting of sulfaritnidine and sulfonamide Of the class consisting Of Sulfa" quinoxaline; sulfamerazine; sulfamethazine, sulfathiazole; nilaml'de, Sulfathialole, Sulfamerflll'ne, Slllfamethazine, sulfanilamide; sulfadiazine, and sulfaguanidine, said and sulfaqul'noXall'ne, Said miXtlFe being so proportioned diamino-pynmidine and sulfonamide being present in the with respect to its content of diamino-pyrimidine and to composition in a ratio between 1 part diamino-pyrimi- Its colltent of slllf'onamide that a predetermined quantity dine to 20 parts sulfonamide and 1 part diamino-pyrimiof e eempesltlen may be intermixed with a p dine to 0.5 part sulfonamide, termmed quantity of an ingestive vehicle to form a poul- 5. A chemotherapeutic compositon for the control of try ratlon on which P y y feed ad l m Without coccidiosis in poultry which comprises a mixture f a 40 intolerable toxic effect and which will contain the di diamino-pyrimidlne selected from the class consisting of ammo-pyrimidine and Sulfollaml'de in efiective dosage 2,4-diamino-5-(p-chlorophenyl)-6-methyl pyrimidine; 2,4 m u but not exceeding Pe y Weight of diamino-S-(p-chlorophenyl)-6-ethyl pyrimidine; 2,4-did1a rr11ne-pyrnnidine and not exceeding percent by amino-S-(p-chlorophenyl)-6-n-propyl pyrimidine; 2,4-dir Welght of Sulfonaml'deamin0 6 n amy1 5-{p-chloroPhewU.pyrimidine; 2 i 4Q 11 Achemotherapeutic composition for combatting i 5 3g42 1 1 and coccidiosis in poultry which may be diluted with a non 2 4 1 5 i and toxic ingestive carrier vehicle for oral administration to sulfonamide selected from the class consisting of sulfah Poultry comprisingamiXiure ntaining sulfaquinoxaquinoxaline; sulfamerazine; sulfamethazine, sulfathiazole; 11 I1e a n -(phl rophenyl)-6-ethy1 pyrimisulfanilamide; sulfadiazine, and sulfaguanidine, said dme 1n fl1e ratlo of two Parts to tell Parts y Weight of diamino-pyrlmidine and sulfonamide being present in sulfaqumoxahne to 1 P y Weight of Sai i minoture is orally administered by ad libitum f di to the toxic ingestive carrier vehicle for oral administration to poultry in an ingestive carrier vehicle in which said i Poultry comprisingaml'Xture Conta ning sulfaquinoxamixture is present in a concentration between .0005% 11,116 and -py imiand 5% dine in the ratio of ten parts by weight of sulfaquinoxa- 6. A chemotherapeutic composition effective to con- 11116 to one P y Weight of said diaminoyn jdi trol COCCldlOSlS in poultry when orally admimstered at non-toxic use levels which comprises a combination of References Cited m the file of thls patent 2,4-diamino-5-(p-chlorophenyl)-6-ethyl pyrimidine and Seidenl Chemist, 21, 4, April 1950, PP- sulfaquinoxaline; there being present in the composition 0.1 to 3 parts by Weight of said diamino-pyrimidine to 1 F3160 et of Pharmacoland Chemothel' part by weight of said sulfaquinoxaline. 65 VOL 6, 1951, PP- part- PP A composition efiective to control coccidiosis in Gl'eellberg 6t of Pharmacoland P The!" poultry which composition when diluted with a non- 99, 4, Augllst 1950, PP- -4 9- toxic ingestive comestible carrier will provide an etfec- Eyles et Health P VOL March tive dosage when orally administered by feeding it ad 1952 PP- P -PP- libitum to the poultry in the comestible at non-toxic use Chandler: Ifltmdt0 Parasitology, 8th 50, 1011!! levels, said composition comprising a mixture of' a Wiley, PP- 219 and 220. 

1. A RATION FOR AD LIBITUM FEEDING TO A FLOCK OF POULTRY TO COMBAT THE DISEASE OF COCCIDIOSIS IN THE POULTRY FLOCK WITHOUT INTOLERABLE TOXIC EFFECT UPON THE POULTRY WHICH COMPRISES A POULTRY FEEDING MASH IN WHICH IS INCOROPATED NOT LESS THAN 9002 PERCENT AND NOT MORE THAN .05 PERCENT BY WEIGHT OF A DIAMINO-PYRIMIDINE HAVING THE FORMULA: 